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1
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Amadio P, Sandrini L, Zarà M, Barbieri SS, Ieraci A. NADPH-oxidases as potential pharmacological targets for thrombosis and depression comorbidity. Redox Biol 2024; 70:103060. [PMID: 38310682 PMCID: PMC10848036 DOI: 10.1016/j.redox.2024.103060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 01/23/2024] [Accepted: 01/24/2024] [Indexed: 02/06/2024] Open
Abstract
There is a complex interrelationship between the nervous system and the cardiovascular system. Comorbidities of cardiovascular diseases (CVD) with mental disorders, and vice versa, are prevalent. Adults with mental disorders such as anxiety and depression have a higher risk of developing CVD, and people with CVD have an increased risk of being diagnosed with mental disorders. Oxidative stress is one of the many pathways associated with the pathophysiology of brain and cardiovascular disease. Nicotinamide adenine dinucleotide phosphate oxidase (NOX) is one of the major generators of reactive oxygen species (ROS) in mammalian cells, as it is the enzyme that specifically produces superoxide. This review summarizes recent findings on the consequences of NOX activation in thrombosis and depression. It also discusses the therapeutic effects and pharmacological strategies of NOX inhibitors in CVD and brain disorders. A better comprehension of these processes could facilitate the development of new therapeutic approaches for the prevention and treatment of the comorbidity of thrombosis and depression.
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Affiliation(s)
- Patrizia Amadio
- Unit of Brain-Heart Axis: Cellular and Molecular Mechanisms, Centro Cardiologico Monzino IRCCS, 20138, Milan, Italy
| | - Leonardo Sandrini
- Unit of Brain-Heart Axis: Cellular and Molecular Mechanisms, Centro Cardiologico Monzino IRCCS, 20138, Milan, Italy
| | - Marta Zarà
- Unit of Brain-Heart Axis: Cellular and Molecular Mechanisms, Centro Cardiologico Monzino IRCCS, 20138, Milan, Italy
| | - Silvia S Barbieri
- Unit of Brain-Heart Axis: Cellular and Molecular Mechanisms, Centro Cardiologico Monzino IRCCS, 20138, Milan, Italy.
| | - Alessandro Ieraci
- Department of Theoretical and Applied Sciences, eCampus University, 22060, Novedrate (CO), Italy; Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, 20156, Milan, Italy.
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Bontekoe J, Matsumura J, Liu B. Thrombosis in the pathogenesis of abdominal aortic aneurysm. JVS Vasc Sci 2023; 4:100106. [PMID: 37564632 PMCID: PMC10410173 DOI: 10.1016/j.jvssci.2023.100106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 03/23/2023] [Indexed: 08/12/2023] Open
Abstract
Background Abdominal aortic aneurysms (AAAs) are a relatively common vascular pathology of the elderly with high morbidity potential. Irreversible degeneration of the aortic wall leads to lethal rupture if left untreated. Nearly all AAAs contain intraluminal thrombus (ILT) to a varying degree, yet the mechanisms explaining how thrombosis is disturbed in AAA are relatively unknown. This review examined the thrombotic complications associated with AAA, the impact of thrombosis on AAA surgical outcomes and AAA pathogenesis, and the use of antithrombotic therapy in the management of this disease. Methods A literature search of the PubMed database was conducted using relevant keywords related to thrombosis and AAAs. Results Thrombotic complications are relatively infrequent in AAA yet carry significant morbidity risks. The ILT can impact endovascular aneurysm repair by limiting anatomic suitability and influence the risk of endoleaks. Many of the pathologic mechanisms involved in AAA development, including hemodynamics, inflammation, oxidative stress, and aortic wall remodeling, contain pathways that interact with thrombosis. Conversely, the ILT can also be a source of biochemical stress and exacerbate these aneurysmal processes. In animal AAA models, antithrombotic therapies have shown favorable results in preventing and stabilizing AAA. Antiplatelet agents may be beneficial for reducing risks of major adverse cardiovascular events in AAA patients; however, neither antiplatelet nor anticoagulation is currently used solely for the management of AAA. Conclusions Thrombosis and ILT may have detrimental effects on AAA growth, rupture risk, and patient outcomes, yet there is limited understanding of the pathologic thrombotic mechanisms in aneurysmal disease at the molecular level. Preventing ILT using platelet and coagulation inhibitors may be a reasonable theoretical target for aneurysm progression and stability; however, the practical benefits of current antithrombotic therapies in AAA are unclear. Further research is needed to demonstrate the extent to which thrombosis impacts AAA pathogenesis and to develop novel pharmacologic strategies for the medical management of this disease.
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Affiliation(s)
- Jack Bontekoe
- Division of Vascular Surgery, Department of Surgery, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI
| | - Jon Matsumura
- Division of Vascular Surgery, Department of Surgery, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI
| | - Bo Liu
- Division of Vascular Surgery, Department of Surgery, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI
- Department of Cellular and Regenerative Biology, University of Wisconsin-Madison School of Medicine and Public Health, Madison, WI
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Tarantino G, Citro V, Capone D, Gaudiano G, Sinatti G, Santini SJ, Balsano C. Copper concentrations are prevalently associated with antithrombin III, but also with prothrombin time and fibrinogen in patients with liver cirrhosis: A cross-sectional retrospective study. J Trace Elem Med Biol 2021; 68:126802. [PMID: 34091123 DOI: 10.1016/j.jtemb.2021.126802] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 04/21/2021] [Accepted: 05/27/2021] [Indexed: 11/25/2022]
Abstract
BACKGROUND Concerning the link between copper excess and the pathogenesis of chronic liver diseases, its retention is reckoned to develop as a complication of cholestasis. Recently, it has been found that cholestatic liver injury involves largely inflammatory cell-mediated liver cell necrosis, with consequent reduced hepatic mass, more than occurring through direct bile acid-induced apoptosis. On the other hand, interference with protein synthesis could be expected to result, ending in an altered ability of the liver to retain copper. Little is known about the association between serum copper and clotting factors in cirrhotics. We aimed at studying a possible relationship between increased levels of copper and an aspect of the haemostatic process in liver cirrhosis patients, assessing an index of protein synthesis (albumin) and parameters of protein synthesis/coagulation/fibrinolysis, such as prothrombin time (PT), antithrombin (AT) III and fibrinogen. METHODS Records from 85 patients suffering from liver cirrhosis of various aetiology and different severity were retrospectively examined. Serum concentrations of copper were determined by atomic absorption spectrophotometer. An index of protein synthesis, such as albumin and parameters of both synthesis and coagulation/hypercoagulation such as PT %, AT III%, levels of fibrinogen were taken into account to study possible correlations to serum copper. The severity of cirrhosis was evaluated by the Child-Pugh (C-P) classification. The relationship among variables were studied by linear regression. RESULTS Copper levels of patients suffering from liver cirrhosis were increased respect to those of controls, 102.7+/-28.7 versus 80.4+/-19.5 mcg/dL, (P = .0009), independently from disease severity, and were positively predicted by PT% (P = 0. 017), fibrinogen (P = 0.007) and AT III% (P = 0.000), at linear regression. Among the previous parameters, to which serum albumin was added, the unique predictor of copper levels was AT III%, at multiple regression (P = 0. 010); AT III% was negatively predicted by the C-P classification (P = 0.000); copper levels, adjusted for C-P classification, were predicted by AT III% (P = 0.020) and fibrinogen concentrations, but not by PT% (P = 0.09). CONCLUSION The copper concentration is reckoned as responsible for production of the hydroxyl radicals. On the basis that oxidants may enhance the activity of the extrinsic coagulation cascade, ultimately leading to thrombin formation, via their combined effects on stimulation of tissue factor activity and inhibition of fibrinolytic pathways, the positive relationship of copper to coagulation/hypercoagulation parameters (mainly AT III) in our research could find a plausible interpretation.
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Affiliation(s)
- Giovanni Tarantino
- Department of Clinical Medicine and Surgery, Federico II University Medical School of Naples, 80131, Naples, Italy.
| | - Vincenzo Citro
- Department of General Medicine, "Umberto I" Hospital, 84014, Nocera Inferiore (SA), Italy
| | | | - Giuseppe Gaudiano
- Clinical Pathology Unit,"Umberto I" Hospital, 84014, Nocera Inferiore (SA), Italy
| | - Gaia Sinatti
- Department of Clinical Medicine, Life, Health & Environmental Sciences-MESVA, University of L'Aquila, 67100 L, Aquila, Italy
| | - Silvano Junior Santini
- Department of Clinical Medicine, Life, Health & Environmental Sciences-MESVA, University of L'Aquila, 67100 L, Aquila, Italy
| | - Clara Balsano
- Department of Clinical Medicine, Life, Health & Environmental Sciences-MESVA, University of L'Aquila, 67100 L, Aquila, Italy
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Pravda J. Sepsis: Evidence-based pathogenesis and treatment. World J Crit Care Med 2021; 10:66-80. [PMID: 34316443 PMCID: PMC8291008 DOI: 10.5492/wjccm.v10.i4.66] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 04/13/2021] [Accepted: 06/02/2021] [Indexed: 02/06/2023] Open
Abstract
Sepsis can develop during the body’s response to a critical illness leading to multiple organ failure, irreversible shock, and death. Sepsis has been vexing health care providers for centuries due to its insidious onset, generalized metabolic dysfunction, and lack of specific therapy. A common factor underlying sepsis is the characteristic hypermetabolic response as the body ramps up every physiological system in its fight against the underlying critical illness. A hypermetabolic response requires supraphysiological amounts of energy, which is mostly supplied via oxidative phosphorylation generated ATP. A by-product of oxidative phosphorylation is hydrogen peroxide (H2O2), a toxic, membrane-permeable oxidizing agent that is produced in far greater amounts during a hypermetabolic state. Continued production of mitochondrial H2O2 can overwhelm cellular reductive (antioxidant) capacity leading to a build-up within cells and eventual diffusion into the bloodstream. H2O2 is a metabolic poison that can inhibit enzyme systems leading to organ failure, microangiopathic dysfunction, and irreversible septic shock. The toxic effects of H2O2 mirror the clinical and laboratory abnormalities observed in sepsis, and toxic levels of blood H2O2 have been reported in patients with septic shock. This review provides evidence to support a causal role for H2O2 in the pathogenesis of sepsis, and an evidence-based therapeutic intervention to reduce H2O2 levels in the body and restore redox homeostasis, which is necessary for normal organ function and vascular responsiveness.
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Affiliation(s)
- Jay Pravda
- Inflammatory Disease Research Centre, Therashock LLC, Palm Beach Gardens, FL 33410, United States
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Manchanda R, Fernandez-Fernandez A, Paluri SLA, Smith BR. Nanomaterials to target immunity. ADVANCES IN PHARMACOLOGY 2021; 91:293-335. [PMID: 34099112 DOI: 10.1016/bs.apha.2021.03.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Critical advances have recently been made in the field of immunotherapy, contributing to an improved understanding of how to harness and balance the power of immune responses in the treatment of diseases such as cancer, cardiovascular disease, infectious diseases, and autoimmune diseases. Combining nanomedicine with immunotherapy provides the opportunity for customization, rational design, and targeting to minimize side effects and maximize efficacy. This review highlights current developments in the design and utilization of nano-based immunotherapy systems, including how rationally-designed nanosystems can target and modify immune cells to modulate immune responses in a therapeutic manner. We discuss the following topics: targeted immuno-engineered nanoformulations, commercial formulations, clinical applicability, challenges associated with current approaches, and future directions.
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Affiliation(s)
- Romila Manchanda
- Department of Biomedical Engineering, Michigan State University, East Lansing, MI, United States; Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI, United States
| | - Alicia Fernandez-Fernandez
- Dr. Pallavi Patel College of Health Care Sciences, Nova Southeastern University, Ft. Lauderdale, FL, United States
| | - Sesha Lakshmi Arathi Paluri
- Department of Biomedical Engineering, Michigan State University, East Lansing, MI, United States; Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI, United States
| | - Bryan Ronain Smith
- Department of Biomedical Engineering, Michigan State University, East Lansing, MI, United States; Institute for Quantitative Health Science and Engineering, Michigan State University, East Lansing, MI, United States.
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Lucas ML, Carraro CC, Belló-Klein A, Kalil AN, Aerts N. Oxidative Stress in Human Aorta of Patients with Advanced Aortoiliac Occlusive Disease. Braz J Cardiovasc Surg 2017; 31:428-433. [PMID: 28076619 PMCID: PMC5407147 DOI: 10.5935/1678-9741.20160086] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Accepted: 09/30/2016] [Indexed: 01/21/2023] Open
Abstract
Introduction Oxidative stress seems to be a role in the atherosclerosis process, but research in human beings is scarce. Objective To evaluate the role of oxidative stress on human aortas of patients submitted to surgical treatment for advanced aortoiliac occlusive disease. Methods Twenty-six patients were divided into three groups: control group (n=10) formed by cadaveric organ donors; severe aortoiliac stenosis group (patients with severe aortoiliac stenosis; n=9); and total aortoiliac occlusion group (patients with chronic total aortoiliac occlusion; n=7). We evaluated the reactive oxygen species concentration, nicotinamide adenine dinucleotide phosphate-oxidase, superoxide dismutase and catalase activities as well as nitrite levels in samples of aortas harvested during aortofemoral bypass for treatment of advanced aortoiliac occlusive disease. Results We observed a higher level of reactive oxygen species in total aortoiliac occlusion group (48.3±9.56 pmol/mg protein) when compared to severe aortoiliac stenosis (33.5±7.4 pmol/mg protein) and control (4.91±0.8 pmol/mg protein) groups (P<0.05). Nicotinamide adenine dinucleotide phosphate oxidase activity was also higher in total aortoiliac occlusion group when compared to the control group (3.81±1.7 versus 1.05±0.31 µmol/min.mg protein; P<0.05). Furthermore, superoxide dismutase and catalase activities were significantly higher in the severe aortoiliac stenosis and total aortoiliac occlusion groups when compared to the control cases (P<0.05). Nitrite concentration was smaller in the severe aortoiliac stenosis group in comparing to the other groups. Conclusion Our results indicated an increase of reactive oxygen species levels and nicotinamide adenine dinucleotide phosphate-oxidase activity in human aortic samples of patients with advanced aortoiliac occlusive disease. The increase of antioxidant enzymes activities may be due to a compensative phenomenon to reactive oxygen species production mediated by nicotinamide adenine dinucleotide phosphate oxidase. This preliminary study offers us a more comprehensive knowledge about the role of oxidative stress in advanced aortoiliac occlusive disease in human beings.
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Affiliation(s)
| | | | | | | | - Newton Aerts
- Universidade Federal de Ciências da Saúde (UFCSPA), Porto Alegre, RS, Brazil
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Ramakrishna G, Rooke TW, Cooper LT. Iron and peripheral arterial disease: revisiting the iron hypothesis in a different light. Vasc Med 2016; 8:203-10. [PMID: 14989563 DOI: 10.1191/1358863x03vm493ra] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
The relationship between iron status and atherosclerosis has long been a topic of debate in the literature. Despite more than 25 years of research, there is no consensus regarding a causal relationship. To date, the vast majority of studies have focused on iron burden with respect to a hypothesized role in the onset and progression of coronary artery disease. However, the effect of iron in the coronary arterial system may differ mechanistically and therefore clinically from its effect in the peripheral arterial system. This review will summarize the biochemical, pathologic, animal, and clinical research data with respect to iron and atherosclerosis. This background will be expanded upon to provide insights into ongoing studies and paths for future investigations into the role of iron and peripheral arterial disease.
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Affiliation(s)
- Gautam Ramakrishna
- Department of Internal Medicine, Division of Cardiovascular Diseases, Mayo Clinic and Foundation, Rochester, MN 55905, USA
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8
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Laviano A, Rossi Fanelli F. Lipid emulsions in parenteral nutrition: does one size fits all? SOUTH AFRICAN JOURNAL OF CLINICAL NUTRITION 2016. [DOI: 10.1080/16070658.2010.11734260] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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9
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Ilic MD, Pavlovic R, Lazarevic G, Zivanovic S, Cvetkovic T, Kocic G, Ilic S, Ambrosio G. Detrimental effects of a bout of physical exercise on circulating endogenous inhibitors of endothelial function in patients with coronary artery disease. J Cardiovasc Med (Hagerstown) 2016; 18:610-616. [PMID: 27168139 DOI: 10.2459/jcm.0000000000000400] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND A bout of intense physical activity has been shown to transiently impair endothelial function; however, the underlying mechanisms are unclear. AIM The purpose of the review was to assess the impact of a bout of physical exercise induced by exercise stress echocardiography, on blood concentration of the endogenous inhibitors of nitric oxide synthase, asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA), in patients with atherosclerosis. METHODS Overall, 83 study participants were enrolled, 25 coronary artery disease (CAD) patients, 20 age and sex-matched asymptomatic study participants with at least one risk factor for CAD, and 38 healthy controls. RESULTS Patients with CAD developed symptoms and/or left ventricular wall motion abnormalities during exercise; no changes were seen in study participants with risk factors, or in healthy controls. At baseline, in CAD patients and in study participants with risk factors, both ADMA and SDMA were higher than healthy controls (P < 0.001). However, a further large increase occurred during exercise stress echocardiography in both groups, regardless of development of symptoms (P < 0.001). CONCLUSION Basal concentrations of ADMA and SDMA are high in CAD patients and in study participants with risk factors, consistent with impaired nitric oxide synthase activity in atherosclerosis. Large increase of these endogenous inhibitors of nitric oxide during intense exercise provide support to the hypothesis that in patients with atherosclerosis endothelial function may further deteriorate as a consequence of a bout of physical activity.
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Affiliation(s)
- Marina Deljanin Ilic
- aInstitute of Cardiology bFaculty of Medicine, Institute of Chemistry, University of Nis cClinic of Cardiology, Clinical Center dFaculty of Medicine, Institute of Biochemistry eDivision of Cardiology, University of Perugia School of Medicine, Perugia, Italy; Faculty of Medicine, University of Nis, Nis, Serbia
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Qin YR, You SJ, Zhang Y, Li Q, Wang XH, Wang F, Hu LF, Liu CF. Hydrogen sulfide attenuates ferric chloride-induced arterial thrombosis in rats. Free Radic Res 2016; 50:654-65. [PMID: 26982248 DOI: 10.3109/10715762.2016.1164311] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Affiliation(s)
- Yi-Ren Qin
- Department of Neurology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, The Second Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Neuroscience, Soochow University, Suzhou, China
| | - Shou-Jiang You
- Department of Neurology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Yan Zhang
- Department of Neurology, Kunshan Hospital Affiliated to Jiangsu University, Kunshan, China
| | - Qian Li
- Institute of Neuroscience, Soochow University, Suzhou, China
- Department of Pharmacology, School of Pharmaceutical Science, Soochow University, Suzhou, China
| | - Xian-Hui Wang
- Department of Neurology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Fen Wang
- Institute of Neuroscience, Soochow University, Suzhou, China
| | - Li-Fang Hu
- Department of Neurology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, The Second Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Neuroscience, Soochow University, Suzhou, China
- Department of Pharmacology, School of Pharmaceutical Science, Soochow University, Suzhou, China
| | - Chun-Feng Liu
- Department of Neurology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, The Second Affiliated Hospital of Soochow University, Suzhou, China
- Institute of Neuroscience, Soochow University, Suzhou, China
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11
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Hyperuricemia reflects global Fontan pathophysiology and associates with morbidity and mortality in patients after the Fontan operation. Int J Cardiol 2015; 184:623-630. [DOI: 10.1016/j.ijcard.2015.02.026] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2014] [Revised: 02/15/2015] [Accepted: 02/21/2015] [Indexed: 01/23/2023]
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12
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Pravda J. Metabolic theory of septic shock. World J Crit Care Med 2014; 3:45-54. [PMID: 24892019 PMCID: PMC4038812 DOI: 10.5492/wjccm.v3.i2.45] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 01/21/2014] [Accepted: 03/04/2014] [Indexed: 02/06/2023] Open
Abstract
Septic shock is a life threatening condition that can develop subsequent to infection. Mortality can reach as high as 80% with over 150000 deaths yearly in the United States alone. Septic shock causes progressive failure of vital homeostatic mechanisms culminating in immunosuppression, coagulopathy and microvascular dysfunction which can lead to refractory hypotension, organ failure and death. The hypermetabolic response that accompanies a systemic inflammatory reaction places high demands upon stored nutritional resources. A crucial element that can become depleted early during the progression to septic shock is glutathione. Glutathione is chiefly responsible for supplying reducing equivalents to neutralize hydrogen peroxide, a toxic oxidizing agent that is produced during normal metabolism. Without glutathione, hydrogen peroxide can rise to toxic levels in tissues and blood where it can cause severe oxidative injury to organs and to the microvasculature. Continued exposure can result in microvascular dysfunction, capillary leakage and septic shock. It is the aim of this paper to present evidence that elevated systemic levels of hydrogen peroxide are present in septic shock victims and that it significantly contributes to the development and progression of this frequently lethal condition.
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Soyingbe OS, Oyedeji A, Basson AK, Opoku AR. The Essential Oil of <i>Eucalyptus grandis</i> W. Hill ex Maiden Inhibits Microbial Growth by Inducing Membrane Damage. Chin Med 2013. [DOI: 10.4236/cm.2013.41002] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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Kvietys PR, Granger DN. Role of reactive oxygen and nitrogen species in the vascular responses to inflammation. Free Radic Biol Med 2012; 52:556-592. [PMID: 22154653 PMCID: PMC3348846 DOI: 10.1016/j.freeradbiomed.2011.11.002] [Citation(s) in RCA: 223] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2011] [Revised: 11/04/2011] [Accepted: 11/04/2011] [Indexed: 12/23/2022]
Abstract
Inflammation is a complex and potentially life-threatening condition that involves the participation of a variety of chemical mediators, signaling pathways, and cell types. The microcirculation, which is critical for the initiation and perpetuation of an inflammatory response, exhibits several characteristic functional and structural changes in response to inflammation. These include vasomotor dysfunction (impaired vessel dilation and constriction), the adhesion and transendothelial migration of leukocytes, endothelial barrier dysfunction (increased vascular permeability), blood vessel proliferation (angiogenesis), and enhanced thrombus formation. These diverse responses of the microvasculature largely reflect the endothelial cell dysfunction that accompanies inflammation and the central role of these cells in modulating processes as varied as blood flow regulation, angiogenesis, and thrombogenesis. The importance of endothelial cells in inflammation-induced vascular dysfunction is also predicated on the ability of these cells to produce and respond to reactive oxygen and nitrogen species. Inflammation seems to upset the balance between nitric oxide and superoxide within (and surrounding) endothelial cells, which is necessary for normal vessel function. This review is focused on defining the molecular targets in the vessel wall that interact with reactive oxygen species and nitric oxide to produce the characteristic functional and structural changes that occur in response to inflammation. This analysis of the literature is consistent with the view that reactive oxygen and nitrogen species contribute significantly to the diverse vascular responses in inflammation and supports efforts that are directed at targeting these highly reactive species to maintain normal vascular health in pathological conditions that are associated with acute or chronic inflammation.
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Affiliation(s)
- Peter R Kvietys
- College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - D Neil Granger
- Department of Molecular & Cellular Physiology, Louisiana State University Health Sciences Center, Shreveport, LA 71130-3932, USA.
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Owens AP, Mackman N. Tissue factor and thrombosis: The clot starts here. Thromb Haemost 2010; 104:432-9. [PMID: 20539911 PMCID: PMC3043984 DOI: 10.1160/th09-11-0771] [Citation(s) in RCA: 134] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2009] [Accepted: 03/29/2010] [Indexed: 01/17/2023]
Abstract
Thrombosis, or complications from thrombosis, currently occupies the top three positions in the cardiovascular causes of morbidity and mortality in the developed world. There are a limited number of safe and effective drugs to prevent and treat thrombosis. Animal models of thrombosis are necessary to better understand the complex components and interactions involved in the formation of a clot. Tissue factor (TF) is required for the initiation of blood coagulation and likely plays a key role in both arterial and venous thrombosis. Understanding the role of TF in thrombosis may permit the development of new antithrombotic drugs. This review will focus on the role of TF in in vivo models of thrombosis.
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Affiliation(s)
- A Phillip Owens
- Division of Hematology/Oncology, Department of Medicine, University of North Carolina at Chapel Hill, USA
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Westrick RJ, Winn ME, Eitzman DT. Murine models of vascular thrombosis (Eitzman series). Arterioscler Thromb Vasc Biol 2007; 27:2079-93. [PMID: 17600224 DOI: 10.1161/atvbaha.107.142810] [Citation(s) in RCA: 145] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Thrombotic complications of vascular disease are the leading cause of morbidity and mortality in most industrialized countries. Despite this, safe and effective drugs targeting these complications are limited, especially in the chronic setting. This is because of the complexity of thrombosis in both arteries and veins, which is becoming increasingly evident as numerous factors are now known to affect the fate of a forming thrombus. To fully characterize thrombus formation in these settings, in vivo models are necessary to study the various components and intricate interactions that are involved. Genetic manipulations in mice are greatly facilitating the dissection of relevant pro- and antithrombotic influences. Standardized models for the study of thrombosis in mice as well as evolving techniques that allow imaging of molecular events during thrombus formation are now available. This review will highlight some of the recent developments in the field of thrombosis using mouse models and how these studies are expanding our knowledge of thrombotic disease.
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Affiliation(s)
- Randal J Westrick
- Departments of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
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Ramírez-Prieto MT, García-Río F, Villamor J. [Role of oxidative stress in respiratory diseases and its monitoring]. Med Clin (Barc) 2006; 127:386-96. [PMID: 16987485 DOI: 10.1157/13092440] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Together with inflammation and subsequent remodeling of airways, an imbalance between oxidative and anti-oxidative agents is generated during the development of numerous pulmonary diseases. This process seems to be involved in both the pathogenesis and chronification of asthma, chronic obstructive pulmonary disease (COPD), SOAS, interstitial lung diseases and cystic fibrosis. Reactive oxygen species including superoxide anion, hidroxyl radicals and hydrogen peroxide (H2O2) are synthetised as a response of inflammatory cells and are responsible of the oxidation of nucleic acids, proteins and membrane lipids, leading to cell damage and enhanced inflammation. Until recently, it was difficult to quantify the airway production of reactive oxidative species (ROS). In fact, it has been only in the last few years when it has been possible to determine indirectly the levels of ROS in expired air and in tissue of asthmatic patients. The analysis of exhaled air is a single, reproducible and non-invasive technique which is useful in the study of volatile and non-volatile gases generated in different conditions. The determination of exhaled nitric oxide and carbon monoxide (CO) has a great usefulness in the assessment of asthma. Nitric oxide seems to be closely related to the physiopathology of asthma and COPD. In fact, it is correlated with the levels of sputum eosinophils and with the response to the treatment with steroids. Yet a correlation with the degree of airflow obstruction and the seriousness of the process has not been found. Exhaled CO is another indirect marker of inflammation and it is increased in asthma, COPD, cystic fibrosis and bronchectases. Even though numerous studies have shown its usefulness as a marker of inflammation and in the response to corticosteroids, its clinical application has limitations. In particular, it is not a specific and exclusive marker of oxidative stress and its levels are highly influenced by tobacco smoke. On the other hand, the association between exhaled CO and FEV1 is not clear and no relationship has been proved so far with the improvement of pulmonary function after steroid therapy and with the decrease of maximum expiratory flow at relapses. In this Review, we describe the advances in the knowledge of oxidative stress as a decisive factor in the pathogenesis of prevalent pulmonary diseases, as well as the methods allowing its analysis and monitoring.
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Does the oxidation of methionine in thrombomodulin contribute to the hypercoaguable state of smokers and diabetics? Med Hypotheses 2006; 68:811-21. [PMID: 17064853 DOI: 10.1016/j.mehy.2006.09.009] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2006] [Accepted: 09/03/2006] [Indexed: 01/13/2023]
Abstract
The leading cause of premature death in smokers is cardiovascular disease. Diabetics also suffer from increased cardiovascular disease. This results, in part, from the hypercoagulable state associated with these conditions. However, the molecular cause(s) of the elevated risk of cardiovascular disease and the prothrombotic state of smokers and diabetics remain unknown. It is well known that oxidative stress is increased in both conditions. In smokers, it is established that oxidation of methionine residues takes place in alpha(1)-antitrypsin in lungs and that this leads to emphysema. Thrombomodulin is a key regulator of blood clotting and is found on the endothelium. Oxidation of methionine 388 in thrombomodulin is known to slow the rate at which the thrombomodulin-thrombin complex activates protein C, a protein which, in turn, degrades the factors which activate thrombin and lead to clot formation. In analogy to the cause of emphysema, it is hypothesized that oxidation of this methionine is elevated in smokers relative to non-smokers and, perhaps, in conditions such as diabetes that impose oxidative stress on the body. Evidence for the hypothesis that such an oxidation and concomitant reduction in activated protein C levels would lead to elevated cardiovascular risk is presented.
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Abstract
Hypercholesterolemia is the dominant risk factor associated with atherothrombotic disorders in the western world. Consequently, much attention has been devoted to defining its role in the pathogenesis of atherosclerosis. It is currently recognized that hypercholesterolemia induces phenotypic changes in the microcirculation that are consistent with oxidative and nitrosative stresses. Superoxide is generated via several cellular systems and, once formed, participates in a number of reactions, yielding various free radicals, such as hydrogen peroxide, peroxynitrite, or oxidized low-density lipoproteins. Once oxidant stress is invoked, characteristic pathophysiologic features ensue, such as platelet activation and lipid peroxidation, which are both involved in the initiation and progression of the atherosclerotic lesions. Thus, therapeutic strategies that act to maintain the normal balance in the oxidant status of the vascular bed may prove effective in reducing the deleterious consequences of hypercholesterolemia.
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Affiliation(s)
- Patrizia Ferroni
- Department of Experimental Medicine and Pathology, University La Sapienza, 00161 Rome, Italy
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Thomas-Gibson S, Jawhari A, Atlan P, Brun ALAL, Farthing M, Forbes A. Safe and efficacious prolonged use of an olive oil-based lipid emulsion (ClinOleic©) in chronic intestinal failure. Clin Nutr 2004; 23:697-703. [PMID: 15297108 DOI: 10.1016/j.clnu.2003.11.007] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2003] [Accepted: 11/18/2003] [Indexed: 10/26/2022]
Abstract
BACKGROUND & AIMS Injectable lipid emulsion is an important component of parenteral nutrition. ClinOleic is a lipid emulsion composed of olive oil (80%) and soybean oil (20%). This study evaluated the efficacy and safety of ClinOleic in adults already receiving parenteral nutrition, comparing it to their usual lipid (soybean-oil-based). METHODS Thirteen adults dependent on home parenteral nutrition were recruited from a single hospital. ClinOleic was administered for 6 months. Two-monthly assessments were made. In addition, clinical and adverse events were recorded for 6-month periods before, during and after the study. RESULTS Total numbers of important complications for the 6 months before, during and after the study were 13, 9 and 9, respectively. There were, respectively, 5, 3 and 2 line infections, and 2, 0 and 5 thrombotic episodes in the 3 periods. The numbers of unplanned admissions were, respectively, 8, 5 and 7, with in-patient days accounting for 3.4%, 1.5%, and 2.6% of feeding days, respectively. One patient died (pneumonia). One new case of cholecystolithiasis appeared. CONCLUSION ClinOleic may be used as a safe alternative to standard soybean-oil-based lipid emulsions.
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Peng L, Mundada L, Stomel JM, Liu JJ, Sun J, Yet SF, Fay WP. Induction of heme oxygenase-1 expression inhibits platelet-dependent thrombosis. Antioxid Redox Signal 2004; 6:729-35. [PMID: 15242554 DOI: 10.1089/1523086041361677] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Heme oxygenase-1 (HO-1) plays a key role in protecting tissue from oxidative stress. Although some studies implicate HO-1 in modulating thrombosis after vascular injury, the impact of HO-1 on the rate of clot formation in vivo is poorly defined. This study examined the potential function of HO-1 in regulating platelet-dependent arterial thrombosis. Platelet-rich thrombi were induced in C57BL/6J mice by applying 10% ferric chloride to the exposed carotid artery. Mean occlusion time of wild-type mice (n = 10) was 14.6 +/- 1.0 min versus 12.9 +/- 0.6 min for HO-1-/- mice (n = 11, p = 0.17). However, after challenge with hemin, mean occlusion time was significantly longer in wild-type mice (16.3 +/- 1.2 min, n = 15) than HO-1-/- mice (12.0 +/- 1.0 min, n = 9; p = 0.021). Hemin administration induced an approximately twofold increase in oxidative stress, measured as plasma thiobarbituric acid reactive substances. Immunohistochemical analysis revealed that hemin induced a robust increase in HO-1 expression within the carotid arterial wall. Ex vivo blood clotting within a collagen-coated perfusion chamber was studied to determine whether the accelerated thrombosis observed in HO-1-/- mice was contributed to by effects on the blood itself. Under basal conditions, mean clot formation during perfusion of blood over collagen did not differ between wild-type mice and HO-1-/- mice. However, after hemin challenge, mean clot formation was significantly increased in HO-1-/- mice compared with wild-type controls. These results suggest that, under basal conditions, HO-1 does not exert a significant effect on platelet-dependent clot formation in vivo. However, under conditions that stimulate HO-1 production, platelet-dependent thrombus formation is inhibited by HO-1. Enhanced HO-1 expression in response to oxidative stress may represent an adaptive response mechanism to down-regulate platelet activation under prothrombotic conditions.
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Lindenblatt N, Bordel R, Schareck W, Menger MD, Vollmar B. Vascular heme oxygenase-1 induction suppresses microvascular thrombus formation in vivo. Arterioscler Thromb Vasc Biol 2004; 24:601-6. [PMID: 14739126 DOI: 10.1161/01.atv.0000118279.74056.8a] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
OBJECTIVE By heme degradation, heme oxygenase-1 (HO-1) provides endogenous carbon monoxide and bilirubin, both of which play major roles in vascular biology. The current study aimed to examine whether induction of HO-1 and its byproducts modulate the process of microvascular thrombus formation in vivo. METHODS AND RESULTS In individual microvessels of mouse cremaster muscle preparations, ferric chloride-induced thrombus formation was analyzed using intravital fluorescence microscopy. When mice were pretreated with an intraperitoneal injection of hemin, a HO-1 inducer, immunohistochemistry and Western blot protein analysis of cremaster muscle tissue displayed a marked induction of HO-1. In these animals, superfusion with ferric chloride solution induced arteriolar and venular thrombus formation, which, however, was significantly delayed when compared with thrombus formation in animals without HO-1 induction. The delay in thrombus formation in hemin-treated mice was completely blunted by tin protoporphyrin-IX, a HO-1 inhibitor, but not by copper protoporphyrin-IX, which does not inhibit the enzyme. Coadministration of the vitamin E analogue Trolox in HO-1-blocked animals almost completely restored the delay in thrombus formation, implying that, besides CO, the antioxidant HO pathway metabolite bilirubin mainly contributes to the antithrombotic property of HO-1. This was further supported by the fact that bilirubin was found as effective as hemin in delay of ferric chloride-induced thrombus formation. Animals with HO-1 induction revealed reduced P-selectin protein expression in cremaster muscle tissue, which most probably presented the molecular basis for delayed thrombus growth. CONCLUSIONS Local induction of HO-1 activity may be of preventive and therapeutic value for clinical disorders with increased risk of thrombotic events.
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Affiliation(s)
- N Lindenblatt
- Department of Experimental Surgery, University of Rostock, Rostock, Germany
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25
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Desideri G, Bravi MC, Tucci M, Croce G, Marinucci MC, Santucci A, Alesse E, Ferri C. Angiotensin II inhibits endothelial cell motility through an AT1-dependent oxidant-sensitive decrement of nitric oxide availability. Arterioscler Thromb Vasc Biol 2003; 23:1218-23. [PMID: 12763763 DOI: 10.1161/01.atv.0000078521.51319.65] [Citation(s) in RCA: 41] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVE The migratory capability of vascular endothelial cells plays a pivotal role in the maintenance of vessel wall integrity and is stimulated by nitric oxide (NO). Angiotensin II increases NAD(P)H oxidase activity in endothelial cells, thereby promoting reactive oxygen species (ROS) generation. Because ROS can both reduce NO synthase activity and increase NO breakdown, thus impairing NO availability in endothelial cells, we evaluated the effect of angiotensin II on human vascular endothelial cell (HUVEC) motility. METHODS AND RESULTS Angiotensin II dose- and time-dependently reduced HUVEC migration. Besides inhibiting HUVEC motility, angiotensin II altered intracellular glutathione redox status. The generation of ROS by cultured HUVECs was significantly increased by angiotensin II. Furthermore, angiotensin II reduced NO metabolite concentrations in culture media. The angiotensin II type 1 receptor antagonist candesartan cilexetil attenuated the inhibitory action exerted by angiotensin II on HUVEC motility, reversed the angiotensin II-induced increase in intracellular oxidative stress, and restored NO availability. Similar effects were exerted by the flavonoid inhibitor diphenylene iodinium and the antioxidant agent N-acetyl-L-cysteine. CONCLUSIONS All together, our data demonstrate that angiotensin II inhibits HUVEC motility by reducing NO availability. Such reduction is due to an angiotensin II type 1 receptor-dependent increment in intracellular ROS generation.
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Affiliation(s)
- Giovambattista Desideri
- Department of Internal Medicine and Public Health, University of L'Aquila, Via Vetoio, Blocco 11, 67100, Coppito, L'Aquila, Italy.
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Day SM, Duquaine D, Mundada LV, Menon RG, Khan BV, Rajagopalan S, Fay WP. Chronic iron administration increases vascular oxidative stress and accelerates arterial thrombosis. Circulation 2003; 107:2601-6. [PMID: 12732602 DOI: 10.1161/01.cir.0000066910.02844.d0] [Citation(s) in RCA: 142] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Iron overload has been implicated in the pathogenesis of ischemic cardiovascular events. However, the effects of iron excess on vascular function and the thrombotic response to vascular injury are not well understood. METHODS AND RESULTS We examined the effects of chronic iron dextran administration (15 mg over 6 weeks) on thrombosis, systemic and vascular oxidative stress, and endothelium-dependent vascular reactivity in mice. Thrombus generation after photochemical carotid artery injury was accelerated in iron-loaded mice (mean time to occlusive thrombosis, 20.4+/-8.5 minutes; n=10) compared with control mice (54.5+/-35.5 minutes, n=10, P=0.009). Iron loading had no effect on plasma clotting, vessel wall tissue factor activity, or ADP-induced platelet aggregation. Acute administration of dl-cysteine, a reactive oxygen species scavenger, completely abrogated the effects of iron loading on thrombus formation, suggesting that iron accelerated thrombosis through a pro-oxidant mechanism. Iron loading enhanced both systemic and vascular reactive oxygen species production. Endothelium-dependent vasorelaxation was impaired in iron-loaded mice, indicating reduced NO bioavailability. CONCLUSIONS Moderate iron loading markedly accelerates thrombus formation after arterial injury, increases vascular oxidative stress, and impairs vasoreactivity. Iron-induced vascular dysfunction may contribute to the increased incidence of ischemic cardiovascular events that have been associated with chronic iron overload.
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Affiliation(s)
- Sharlene M Day
- University of Michigan Medical School, Division of Cardiology, Ann Arbor, USA.
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27
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Abstract
This review describes production and effects of reactive oxygen species (ROS) on airway function. ROS are important in many physiological processes but can also have detrimental effects on airway cells and tissues when produced in high quantities or during the absence of sufficient amounts of anti-oxidants. Therefore, these mediators play a prominent role in the pathogenesis of various inflammatory airway disorders, including asthma. Effects of ROS on airway function in asthma have been studied with isolated airway cells and tissues and with animal models and patients. With the use of inhibitors, transgenic animals and measurements of the release of ROS within the airways, it became clear that oxidative stress contributes to the initiation and worsening of inflammatory respiratory disorders.
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Affiliation(s)
- P A Henricks
- Department of Pharmacology and Pathophysiology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, The Netherlands.
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Sakurai Y, Takatsuka H, Yoshioka A, Matsui T, Suzuki M, Titani K, Fujimura Y. Inhibition of human platelet aggregation by L-amino acid oxidase purified from Naja naja kaouthia venom. Toxicon 2001; 39:1827-33. [PMID: 11600144 DOI: 10.1016/s0041-0101(01)00133-7] [Citation(s) in RCA: 65] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
L-Amino acid oxidase (LAO) widely exists in snake venoms. Purification of LAO from the Naja naja kaouthia (monocellate cobra) venom has been reported (Tan and Swaminathan, 1992), but its structural characterization and physiological function remained to be determined. The function of snake venom LAOs in hemostasis, especially their effect on platelet aggregation, has been controversial. We determined the N-terminal amino acid sequence of the N. n. kaouthia LAO named K-LAO to be DDRRSPLEECFQQNDYEEFLEIAKNGLKKTxNPKHVXxV (38 residues). The protein data base search revealed that the enzyme had high similarities with other snake venom LAOs. Further, platelet aggregation studies revealed that K-LAO functionally did not induce platelet aggregation in a platelet-rich plasma system, but that it inhibited platelet aggregation induced by agonists such as ADP, collagen and ristocetin in a dose-dependent manner. K-LAO diminished platelet aggregation more intensely under low than high shear stress. This inhibitory activity of K-LAO on either ristocetin-induced or shear-induced platelet aggregation was quenched by addition of catalase. These results indicate that K-LAO functions as an inhibitor to platelet aggregation through the formation of hydrogen peroxide. The enzyme may contribute to the development of a severe hematological disorder due to cobra envenomation.
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Affiliation(s)
- Y Sakurai
- Department of Blood Transfusion Medicine, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan
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Seno T, Inoue N, Gao D, Okuda M, Sumi Y, Matsui K, Yamada S, Hirata KI, Kawashima S, Tawa R, Imajoh-Ohmi S, Sakurai H, Yokoyama M. Involvement of NADH/NADPH oxidase in human platelet ROS production. Thromb Res 2001; 103:399-409. [PMID: 11553372 DOI: 10.1016/s0049-3848(01)00341-3] [Citation(s) in RCA: 154] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Platelets play an important role in atherosclerotic and thromboembolic vascular diseases. It has been reported that reactive oxygen species (ROS) could modify platelet function, and platelets themselves have the ability to produce ROS. However, the enzymatic sources of ROS in platelets have not been fully determined. The NADH/NADPH oxidase system was originally identified as the major source of ROS in phagocytes. Recently, it has become evident that this oxidase is functionally expressed not only in phagocytes but also in various cell types. The present study was undertaken to test the hypothesis that NADH/NADPH oxidase might be expressed in human platelets. Lucigenin-enhanced chemiluminescence (L-CL) and electron spin resonance (ESR) method demonstrated that human platelets obtained from healthy volunteers released ROS, and the released ROS were increased by stimulation with 12-O-tetradecanoylphorbol-13-acetate (TPA) or calcium ionophore. Homogenates of human platelets, as well as MEG01 cells, megakaryocytic cell line, had the enzymatic activity to produce superoxide in NADH/NADPH-dependent manners. This enzymatic activity was suppressed by diphenylene iodonium (DPI), an inhibitor of NADH/NADPH oxidase. Western blot analysis demonstrated that platelets and MEG01 cells expressed p22(phox) and p67(phox) proteins, components of NADH/NADPH oxidase. Thus, human platelets have the enzymatic activity of p22(phox)-based NADH/NADPH oxidase, and this oxidase is likely one of the important sources of ROS in platelets.
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Affiliation(s)
- T Seno
- Division of Cardiovascular and Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan
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Abstract
All biomacromolecules are faced with oxidative stress. Oxidation of a protein molecule always induces inactivation of the molecule and introduces a tag to that molecule. These modified protein molecules are prone to degradation in vivo by the proteasome system. Coupling of protein modification and degradation of chemically modified proteins is one of the normal protein turnover pathways in vivo. We call this a 'chemical apoptosis' process, which is one of the early manifestations of programmed cell death. Impairment of the proteasome system leads to accumulation of modified nonfunctional proteins or 'aged proteins' that might cause various clinical syndromes including cataractogenesis, premature aging, neurological degeneration and rheumatoid disease. The metal-catalyzed oxidation of biomacromolecules provides an excellent artificial aging system in vitro. The system is very useful in the characterization of structure and function relationships of proteins (enzymes), especially in those containing metal binding domain(s), because the oxidation is always followed by an affinity cleavage at the metal binding site(s) that allows easy identification and further characterization.
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Affiliation(s)
- T C Chang
- Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan, ROC
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31
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Abstract
D-003 is a mixture of higher primary aliphatic saturated acids purified from sugar cane wax whose main component is octacosanoic acid followed by triacontanoic, dotriacontanoic, and tetratriacontanoic acids. The aim of this study was to evaluate the effects of D-003 on: ex vivo platelet aggregation, arterial thrombosis and bleeding time in rats. In addition, time course of antiplatelet effects of D-003 was also investigated on ex vivo platelet aggregation in guinea-pigs. D-003 (25-200 mg kg(-1)) orally administered at single or repeated doses (3 days) inhibited platelet aggregation induced by collagen (2.2 microg ml(-1)) and ADP (2 micromol l(-1)) in rats, and collagen (0.25 microg ml(-1)) induced aggregation in guinea-pigs in a dose-dependent manner. Single doses of D-003 (5-500 mg kg(-1)) administered orally 2 h before induction of arterial thrombosis significantly inhibited the reduction of rectal temperature. D-003 administered at a single dose (50-200 mg kg(-1)) 2 h before the experiment significantly increased the bleeding time in a dose-dependent manner. The time-course effects of D-003 on platelet aggregation, arterial thrombus formation, and bleeding time showed no effect 0.5 h after dosing, and maximal effects exhibited 1-2 h after treatment, whereas no significant effects were found 4 h after treatment.
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Affiliation(s)
- V Molina
- Center of Natural Products, National Center for Scientific Research, Cubanacan, Havana, Cuba
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Görlach A, Brandes RP, Bassus S, Kronemann N, Kirchmaier CM, Busse R, Schini‐Kerth VB. Oxidative stress and expression of p22phox are involved in the up‐regulation of tissue factor in vascular smooth muscle cells in response to activated platelets. FASEB J 2000. [DOI: 10.1096/fj.99-0857com] [Citation(s) in RCA: 22] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Affiliation(s)
- Agnes Görlach
- Institut für Kardiovaskuläre PhysiologieKlinikum der J. W. Goethe‐Universität60590Frankfurt/MainGermany
| | - Ralf P. Brandes
- Institut für Kardiovaskuläre PhysiologieKlinikum der J. W. Goethe‐Universität60590Frankfurt/MainGermany
| | - Steffen Bassus
- Stiftung Deutsche Klinik für DiagnostikFachbereich Hämostaseologie65191WiesbadenGermany
| | - Nicola Kronemann
- Institut für Kardiovaskuläre PhysiologieKlinikum der J. W. Goethe‐Universität60590Frankfurt/MainGermany
| | - Carl M. Kirchmaier
- Stiftung Deutsche Klinik für DiagnostikFachbereich Hämostaseologie65191WiesbadenGermany
| | - Rudi Busse
- Institut für Kardiovaskuläre PhysiologieKlinikum der J. W. Goethe‐Universität60590Frankfurt/MainGermany
| | - Valérie B. Schini‐Kerth
- Institut für Kardiovaskuläre PhysiologieKlinikum der J. W. Goethe‐Universität60590Frankfurt/MainGermany
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Wu CC, Kuo SC, Lee FY, Teng CM. YC-1 potentiates the antiplatelet effect of hydrogen peroxide via sensitization of soluble guanylate cyclase. Eur J Pharmacol 1999; 381:185-91. [PMID: 10554886 DOI: 10.1016/s0014-2999(99)00577-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
In the present study, we showed that 3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole (YC-1), a nitric oxide (NO)-independent activator of soluble guanylate cyclase, could potentiate H2O2-induced inhibition of platelet aggregation and increase of platelet cGMP levels. The synergistic effect of YC-1 and H2O2 on platelet aggregation and increases of cGMP were almost completely prevented by catalase and a selective soluble guanylate cyclase inhibitor (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), or partially attenuated by the hydroxyl radical scavenger mannitol. In contrast, superoxide dismutase failed to influence H2O2/YC-1-induced inhibition of aggregation. Furthermore, YC-1 could enhance the activation of soluble guanylate cyclase caused by FeSO4/H2O2 and, this effect was prevented markedly by mannitol. These results suggest that YC-1 may enhance the antiaggregatory effect of H2O2 via the sensitization of platelet soluble guanylate cyclase. In addition, this phenomenon is, at least in part, dependent on H2O2-derived hydroxyl radical.
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Affiliation(s)
- C C Wu
- Pharmacological Institute, College of Medicine, National Taiwan University, Taipei
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Abstract
Vascular disease and vasomotor responses are largely influenced by oxidant stress. Superoxide is generated via the cellular oxidase systems, xanthine oxidase, and NADH/NADPH oxidases. Once formed, superoxides participate in a number of reactions, yielding various free radicals such as hydrogen peroxide, peroxynitrite, oxidized low-density lipoprotein, or hypochlorous acid. Numerous cellular antioxidant systems exist to defend against oxidant stress; glutathione and the enzymes superoxide dismutase and glutathione peroxidase are critical for maintaining the redox balance of the cell. However, the redox state is disrupted by certain vascular diseases. It appears that oxidant stress both promotes and is induced by diseases such as hypertension, atherosclerosis, and restenosis as well as by certain risk factors for coronary artery disease including hyperlipidemia, diabetes, and cigarette smoking. Once oxidant stress is invoked, characteristic pathophysiologic features ensue, namely adverse vessel reactivity, vascular smooth muscle cell proliferation, macrophage adhesion, platelet activation, and lipid peroxidation.
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Affiliation(s)
- M Maytin
- Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA
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Abstract
Vitronectin (VN) binds to plasminogen activator inhibitor-1 (PAI-1) and integrins and may play an important role in the vascular response to injury by regulating fibrinolysis and cell migration. However, the role of VN in the earliest response to vascular injury, thrombosis, is not well characterized. The purpose of this study was to test the hypothesis that variation in vitronectin expression alters the thrombotic response to arterial injury in mice. Ferric chloride (FeCl3) injury was used to induce platelet-rich thrombi in mouse carotid arteries. Wild-type (VN +/+, n = 14) and VN-deficient (VN −/−, n = 15) mice, matched for age and gender, were studied. Time to occlusion after FeCl3 injury was determined by application of a Doppler flowprobe to the carotid artery. Occlusion times of VN −/− mice were significantly shorter than those of VN +/+ mice (6.0 ± 1.2 minutesv 17.8 ± 2.3 minutes, respectively, P < .001). Histologic analysis of injured arterial segments showed that thrombi from VN +/+ and VN −/− mice consisted of dense platelet aggregates. In vitro studies of murine VN +/+ andVN −/− platelets showed no significant differences in ADP-induced aggregation, but a trend towards increased thrombin-induced aggregation in VN −/− platelets. Purified, denatured VN inhibited thrombin-induced platelet aggregation, whereas native VN did not. Thrombin times of plasma from VN −/− mice (20.5 ± 2.1 seconds, n = 4) were significantly shorter than those ofVN +/+ mice (34.2 ± 6.7 seconds, n = 4, P < .01), and the addition of purified VN to VN −/− plasma prolonged the thrombin time into the normal range, suggesting that VN inhibits thrombin-fibrinogen interactions. PAI-1-deficient mice (n = 6) did not demonstrate significantly enhanced arterial thrombosis compared with wild-type mice (n = 6), excluding a potential indirect antithrombin function of VN mediated by interactions with PAI-1 as an explanation for the accelerated thrombosis observed in VN−/− mice. These results suggest that vitronectin plays a previously unappreciated antithrombotic role at sites of arterial injury and that this activity may be mediated, at least in part, by inhibiting platelet-platelet interactions and/or thrombin procoagulant activity.
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Minamino T, Kitakaze M, Sanada S, Asanuama H, Kurotobi T, Koretsune Y, Fukunami M, Kuzuya T, Hoki N, Hori M. Increased expression of P-selectin on platelets is a risk factor for silent cerebral infarction in patients with atrial fibrillation: role of nitric oxide. Circulation 1998; 98:1721-7. [PMID: 9788825 DOI: 10.1161/01.cir.98.17.1721] [Citation(s) in RCA: 78] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Platelet activation and decreased levels of nitrite and nitrate (NOx), stable end products of nitric oxide (NO), are reported in patients with atrial fibrillation (AF). We examined the time-course changes in plasma NOx levels and the expression of P-selectin on platelets after the onset of AF in a canine model and determined whether these parameters could be risk factors for silent cerebral infarction in patients with AF. METHODS AND RESULTS AF was induced by rapid atrial pacing in the canine model of AF. Plasma NOx levels were significantly decreased and the levels of P-selectin on platelets and of neutrophil/platelet conjugates were significantly increased after the onset of AF in this model. The in vitro experiments demonstrated that the inhibition of NO synthesis increased the expression of P-selectin on platelets. Plasma NOx levels (19.7+/-2.4 versus 27.5+/-2.8 micromol/L) were significantly lower in 25 patients with AF compared with age- (+/-2 years) and sex-matched control subjects. Conversely, the levels of P-selectin on platelets (7.6+/-0.8% versus 4.8+/-0.7%) and of neutrophil/platelet conjugates (14.8+/-0.9% versus 8.1+/-0.6%) were significantly higher in patients with AF. Multiple regression analysis revealed that increased P-selectin on platelets and advanced age were associated with the number of foci of silent cerebral infarction. CONCLUSIONS An irregular heart rate that is characteristic of AF appeared to blunt NO synthesis. The increased expression of P-selectin on platelets associated with the reduced NO levels was a risk factor for silent cerebral infarction in patients with AF.
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Affiliation(s)
- T Minamino
- First Department of Medicine, Osaka University School of Medicine, Suita, Japan
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